Recent studies have suggested that low density lipoproteins (LDL) which have been modified by oxidation play an important role in the formation of atherosclerotic plaques. Macrophages which take up modified LDL are converted to cholesterol-laden foam cells, a histologic hallmark of early atheromatous lesions. The uptake of these modified LDL are mediated by a cell-surface protein, termed the acetyl-LDL or scavenger receptor. The structure of the cDNA encoding the bovine of modified lipoproteins in human atherosclerosis and the establish the importance of the macrophage and its scavenger receptor to that process, it is necessary to determine the structure of the human scavenger receptor. This will be done by cloning the human cDNA which encodes the receptor. Oligonucleotide probes based on the bovine sequence will be used to screen a cDNA library constructed from a human macrophage cell line, THP-1. Both polymerase chain reaction techniques as well as standard plaque hybridization methods will be employed for this screening. Once the structure of the human cDNA has been determined, this information will be used to synthesize species-specific probes. The probes will be used for two purposes. They will be employed in studies of specimens obtained at autopsy and from surgically removed pathologic specimens in order to assess receptor expression in both vascular and non-vascular human tissues. In addition, the probes will be used to isolate the human genomic DNA encoding the scavenger receptor. The genetic elements responsible for the control of expression of the human scavenger receptor gene will then be determined by DNA sequencing, site- directed mutagenesis of candidate control elements, and transient expressions assays of transcription employing a reporter gene linked to the receptor's upstream regulatory elements. Finally, the cDNA encoding the rabbit scavenger receptor will also be isolated. This work will provide an invaluable reagent for the study of atherosclerosis in one of the best models of the disease currently available, the Watanabe rabbit. The isolation of the human cDNA and genomic DNA and the isolation of the rabbit cDNA encoding the macrophage scavenger should lead to the development of a better understanding of the role of modified lipoproteins in atherosclerosis.